The purpose of this TMRC program is to establish a Center of Excellence focused on understanding all aspects of Visceral Leishmaniasis (VL) due to Leishmania donovani in the current phase of the VL elimination initiative in India, that aims to reduce incidence of clinical disease to a very low level. Many unknowns persist with regard to the feasibility of totally interrupting L. donovani transmission, especially as only 1 out of 10 infections leads to clinical disease. The intent of the scientific group planning this application is to generate a body of knowledge and an investigative team that is ready for any resurgence of the disease, possibly in new endemic areas of the country. We propose three research projects focused on the parameters of transmission and persistence of L.donovani in India. Project 1 will use methods established in prior funding periods for surveillance and monitoring of VL, and use global metabolomics profiling to identify biomarkers of asymptomatic infection, and put this in the context of the gut microbiome and co-infection with other NTDs as risks for progression to VL. Project 2 will monitor the emergence of insecticide resistant populations of Phlebotomus argentipes, the sand fly vector for VL, and examine factors underlying vector competence and the transmissibility of L. donovani from human or animal reservoirs. Project 3 will examine immune factors underlying and contrasting symptomatic VL versus asymptomatic L. donovani infection, both systemically and localized in the skin. The Health and Demographic Surveillance System (HDSS) that was initiated in the current funding period will monitor the demographics and health status of selected populations in Bihar State. Thus, the program will comprehensively examine the extrinsic and intrinsic host factors that underlie the maintenance and continued transmission of VL in Bihar State, India. Aims of the TMRC program are: (1) To maintain and further develop the TMRC as a VL Center of Excellence that addresses knowledge gaps as India progresses toward the goal of disease elimination; (2) To discover environmental and entomological factors that promote disease persistence in the population; (3) To discover human immune factors that determine whether an infected person will develop an asymptomatic or symptomatic outcome; (4) To transform the HDSS into a forward-looking program that is ready for future studies of disease outbreaks, treatment, or immunoprophylaxis of endemic infectious diseases. The research team includes a multi-disciplinary group of investigators sharing the ambition to train the next generation of Indian VL experts. Together the group constitutes a strong team able to move us toward understanding the changing dynamics of transmission of this vector borne disease.